Emerging viruses are a pressing biomedical problem, with the potential to cause significant morbidity and mortality. We aim to reveal the evolutionary processes that allow viruses to jump to, and become established in, new host species. We will continue and extend our work on two well characterized animal viruses that have successfully jumped species barriers to dogs in the recent past and which represent powerful and experimentally tractable models for human emerging viruses; the emergence of canine parvovirus (CPV) from feline panleukopenia virus (FPV), and the cross-species transfer of H3N8 equine influenza A virus (EIV) to dogs that resulted in the emergence of a canine influenza virus (CIV) that has been circulating in a limited fashion in the United States for the past 10 years. We will perform detailed studies to determine the evolutionary interactions between these viruses and the different host species and cell receptors they utilize, and which mediates viral emergence. We will investigate three overlapping areas using a synthesis of comparative and experimental approaches: 1. To define the role of intermediate and parallel hosts in cross-species virus transmission and adaptation. We will examine how the transfer of parvoviruses among multiple carnivore hosts influences their emergence, through the creation of evolutionary 'intermediates' that contain combinations of key host specific mutations, or by generating a wider spectrum of variants with the potential to infect previously resistant hosts. 2. To examine the short-term and long-term evolutionary interplay between viral capsids and the cell receptors of susceptible and resistant hosts. We will study variants of the host transferrin receptor type-1 (TfR) genes in a range of carnivore species that are susceptible to different parvoviruses, and examine the long-term evolutionary arms race between host receptor and viral capsid, including the evolutionary footprints present in endogenous parvoviruses. We will experimentally connect the variation of the TfR with that observed in the viral capsid protein. 3. To determine how the evolutionary trajectory of a virus shapes patterns of cross-species transmission and adaptation. Although H3N8 EIV first emerged in horses from birds in 1963, only in the last ~10 years has it jumped to dogs, and on multiple occasions. We will determine whether the extended passage of EIV in horses altered the likelihood of successful cross-species transmission to dogs, and define the viral genes that influence host tropism for dogs, particularly the evolutionary connections between the host sialic acid receptors and the viral hemagglutinin and neuraminidase genes. PUBLIC HEALTH RELEVANCE: This project addresses one of the central questions in the evolution of infectious disease - the processes that mediate the emergence of viruses in new hosts. The research program proposed is a natural continuation of our work on host-jumping viruses from two different families - parvoviruses and influenza viruses - that represent powerful model systems for understanding disease emergence in humans. In both cases we are uniquely able to examine the ancestral viruses in the original hosts and their spread in the new host following the host jump and over the ensuing decades. By revealing the evolutionary processes that underpin cross- species virus transmission and emergence we will establish general rules that will assist in the control and prevention of future emergent viruses.